Thionyl Chloride → Methyl 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylate

HRID 657397Notes

Reaction equation

HRID 657397 reaction equation
[CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[NH2:25][CH2:26][C:27]1[C:32]([CH2:33][CH3:34])=[N:31][C:30]2[N:35]([CH2:38][CH3:39])[N:36]=[CH:37][C:29]=2[C:28]=1[NH:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>ClCCl>[CH2:38]([N:35]1[C:30]2=[N:31][C:32]([CH2:33][CH3:34])=[C:27]([CH2:26][NH:25][C:8]([C:5]3([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)=[O:10])[C:28]([NH:40][CH:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[C:29]2[CH:37]=[N:36]1)[CH3:39]

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 138618231-(Methoxycarbonyl)cyclopropane-1-carboxylic acidHCID 670055525-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride

Product 1

HCID 57819909Methyl 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To 1-[(methyloxy)carbonyl]cyclopropanecarboxylic acid (7.00 g, 48.5 mmol) in a 250 mL round-bottom flask under nitrogen in dichloromethane (DCM) (75 mL) was added thionyl chloride (19.33 mL, 265 mmol) and the solution heated to reflux. After 1.5 h the solvent and excess thionyl chloride was evaporated off. The clear residue was dissolved in DCM (120 mL), cooled under nitrogen to 0° C. and then diisopropylethylamine (23.13 mL, 132 mmol) was added dropwise. This gave white fumes and a red-brown solution that was stirred in an ice bath while adding 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (15 g, 44.1 mmol) as a solid. After 15 min the icebath was removed. After 2.5 h the reaction was quenched, the mixture was partitioned between dichloromethane and saturated sodium bicarbonate and the aqueous layer extracted well with dichloromethane. The combined organics were washed with water and brine, dried (MgSO4), filtered and evaporated. This gave a dark brown oil/foam, 23.6 g, (>100%). The crude product was purified on a 330 g Companion XL silica cartridge, eluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes. Much of the dark material came straight off the column and product appeared to come off in two broad peaks that were evaporated separately. The early fractions contained the desired product 12.25 g, (65%). HPLC 1.86 min (ret time), 98.4%; LC-MS m/z 430 (M+H)+, 0.79 min (ret time).

Workup

  1. temperaturethe solution heated to reflux
  2. customAfter 1.5 h the solvent and excess thionyl chloride was evaporated off
  3. dissolutionThe clear residue was dissolved in DCM (120 mL)
  4. customAfter 15 min the icebath was removed
  5. customAfter 2.5 h the reaction was quenched
  6. customthe mixture was partitioned between dichloromethane and saturated sodium bicarbonate
  7. extractionthe aqueous layer extracted well with dichloromethane
  8. washThe combined organics were washed with water and brine
  9. dry with materialdried (MgSO4)
  10. filtrationfiltered
  11. customevaporated
  12. customThis gave a dark brown oil/foam, 23.6 g, (>100%)
  13. customThe crude product was purified on a 330 g Companion XL silica cartridge
  14. washeluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes
  15. customwere evaporated separately
  16. customHPLC 1.86 min (ret time), 98.4%
  17. customLC-MS m/z 430 (M+H)+, 0.79 min (ret time)

Sources & evidence

ORD record
ord-25551d62d3ba41528662459fa8f23234
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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